The objective of our proposed research is to investigate the effects of aging on 1) the regulation of the humoral immune response, 2) the induction and maintenance of immunological unresponsiveness, and 3) autoimmunity. Experiments will be designed to investigate the immune status of the cell types involved in each of these immunological states in mice and rabbits of various ages. In the studies on the induction and maintenance of tolerance we will utilize deaggregated human gamma globulin (DHGG) as the tolerogen and strains of mice which differ in their susceptibility to the induction of tolerance. The immune status of thymus-derived (T) and bone marrow-derived (B) cells will be examined under different coditions of tolerance, and attempts will be made to clarify the cellular mechanisms at play in animals at various ages. Since an in vitro model for a primary immune response to HGG has recently been developed, study will be directed at examining the immune status of splenic T and B cells after in vitro induction of tolerance from neonatal, adult and aged mice. Related studies will be directed at the examination of the reported resistance of New Zealand mice to the induction of immunological tolerance. The immune competence of T and B cells from animals at various intervals after birth will also be determined by using 1) cell transfer techniques, 2) immunization with both thymus-dependent and thymus-independent antigens and 3) B cell mitogens as probes for competent B cells. Special emphasis will be placed on observing the reactivity of B cells in young rabbits, since immunocompetency to serum protein antigens in these rabbits develops late after the neonatal period. Other studies will attempt to clarify the cellular mechanisms involved in both the regulation of the immune response and the changes in such regulation upon aging. The information obtained in fulfilling the objectives outlined above will be extrapolated to experimental autoimmune thyroiditis in attempts to clarify some of the putative cellular changes that occur during the aging process which lead the destructive autoimmune processes.